4-methyl-8-(dialkyl aminoalkylamino) quinolines and method for their production



Fatented May 23, 1956 UNITED STATES PATENT. OFFICE 4 METHYL-S- (DIALKYL AMINOALKYL AMINO)QUINOLINES AND METHOD FOR THEIR PRODUCTION Kenneth N. Campbell, Portage Township, St.

Joseph County, Ind., assignor, by mesne assignments, to the United States of America'as represented by the Secretary of War No Drawing. Application April 8, 1946,

Serial No. 660,411v

3 Claims. (01. 260286) in which R represents an alkyl radical having from 2 to 8 carbon atoms which may be either branched or straight chain, R1 represents hydrogen or an alkyl radical having from 1 to 6 carbon atoms, R2 represents an alkyl radical having from 1 to 6 carbon atoms and which may or may not be the same as the R1 substituent, and Rs represents hydrogen or an alkyl radical having from 1 to 4 carbon atoms.

These new substituted lepidines have an antimalarial action which appears in comparison with plasmoquin to have advantages which are not only quantitative, but qualitative. Thus, tests on malaria in monkeys show a remarkable lack of evidence of leukopenia.

.The principal new intermediates are 6alkoxy- B-nitrolepidines represented by the formula and fi-alkoxy-a-aminolepidines represented by the following formula Rao- These new intermediates may be prepared by a drastic condensation of an o-nitro-p-alkoxyaniline and methylvinyl ketone, with arsenic acid" and concentrated sulfuric acid. Preferably, the methylvinyl ketone is supplied by adding a compound, such as 1,3,3-trimethoxybutane (made by the addition of methyl alcohol to monovinylacetylene in the presence of a suitable catalyst as described by Killian, Hennion and Nieuwland,

J. Am. Chem. Soc., vol. 56, page 1786 (1934)),

c-chloroethylmethylketone (which may be prepared by the method of Smith and Sprung, J. Am. Chem. Soc. 65, page 1279 (1934) or 4-methoxybutanone-2 (which may be prepared by the method of Killian, Hennion and Nieuwland, J.

Am. Chem. Soc., 56, 1786 (1934) and i-hydroxy- 2-butanone (which may be prepared by the method of White .and Howard, J. Chem. Soc. (London) 1943, pages 25-31), all of which yield methylvinyl ketone under the reaction conditions. This produces a 6-alkoxy-8-nitrolepidine of Formula 2. This substituted lepidine is reduced, as with hydrogen'under pressure and heat in the presence of a catalyst such as Raney nickel or with stannous chloride, to produce a 6-alkoxy-8- 'aminolepidine of Formula 3;

New 6-alkoxy-8-substituted lepidines of formula 1 may be prepared by condensing a 6- alkoxy-8-aminolepidine, prepared as set forth above, with an alkylamino alkyl halide or the hy'- drohalide thereof, which alkylamino alkyl halide has the following formula bromine and chlorine, to which two elements we confine the term halogen in this specification.

When the halogen is attached to a secondary carbon, it is preferably bromine, to minimize danger of cyclization. The condensation may be 1 carried out by refluxing a mixture of the reactants in a suitable solvent such as a wateralcohol mixture for several hours, desirably in the presence of a buffer such as sodium acetate.

This produces a 6-alkoxy-8-substituted lepidine of Formula 1. It may be separated by diluting the reaction mixture with water, making it alkalinev as with sodium or potassium hydroxide, extracting with ether, and distilling the ether extract in an inert atmosphere at a pressure of 0.5 mm. or less, with a bath temperature of about 225-250 C.

The B-hydroxy-S-substituted lepidines of Formula 1 may be obtained by demethylation of the corresponding G-methoxy compounds.

The substituted lepidines, produced in the form of their iree'basesgare desirably recovered in the; form of their saltsand purifiedas byrecrystallbzation.

The preparation of the 8-nitroand 8-aminot-- lepidines of Formulas 2 and 3-is exemplified as follows:

A mixture of 170 g. of arsenic acid, 50, or water, 168 g. (1.0 mol.) of o-nitro-p-methoxy aniline, and 280 g. of concentratedfsulfuricacid is heated in an oil bath at 1 10415 0., and 1&8 g. (1.0 mol.) of 1,3,3-trimethoxybutarre;added, dropwise in the course of about 2 hours. The mixture is heated at l15l25 Caandstirred tor. an additional two hours, while methanol distill's out. The reaction mixture is then cooled, poured into ice water, and filtered. The filtrate is made asis; with m nium d ox d h c causes the formation of a reddish bro'wn precipitate consisting essentially of the desired 6'-methoxy-' 8 -nitrolepidine, of Formula 2. This product is seperatedby filtration and is recrystallized from- 2llitersofbenzene. Theyield is aboutf- Hg, and tlieproductat' this stage'of purification: melts at 160 165?" C.. It may be further purified, as by re*-- crystallization twice from benzene, to yield a; product melting at about 16515-1115 6.; but it; need not be so purified, and maybe-used as-obtainedirom thefirst crystallization f roinibenzene;

Ajmixture of 33" g. offthefi methoxy ii nitrog lepi'dine, 25ml. of absolute alcohol';.75 ml; oi ethylacet'ate, and, 9' g; of Raney nickel is shalren' with hydrogen at50 C. and 60 lbs/sq; in. The'-theo'-' reticali amountiof hydrogen is absorbed in about 80jjminutes, The reaction mixture is filtered; and the filtrate distilled, to remove the. alcohol and? ethyl acetate, and recover the desiredd-methoxy- 8+am'inolepidine, which boils at about 164 -170 Ciat 3' mm. pressure. This may'berecrystallized' from ligroin, to yield white crystals melting at abouti86L5-8Z5" C.

The preparation of the new; antimalarials is exemplified as follows:

Example 1' 1:.

b?- methoxy 8'- (6f-diethylaminohexylaminqflepidine, represented by the following, formula )2 CHI,

01H! (Q a)l -N{ GiEia may be prepared as follows:-

30 g; of diethylaminohexan'ol adde'd withz g5.-

shak ing to 520 ml. of 48percent hydrobromic acid} and} the solution is refluxed forabout; six hours;v It ls then concentrated to a thickisyruprunden re. duced pressure-at-a temperatureiof about GOeQdt C: The syrup istakenup inwaterand agaiir. 70';

evaporated; The residue consists: essentially: of; 6 -diethylaminohexyl bromide l'iydrobrcmide;. which is recovered by recrystallization from; a. mixture of alcohol and ether. The. product is obtainedin good yield; and meltsat 60 -631 0:

A mixture of 57 g. (0.18 mol.) of diethylaminohexyl bromide hydrobromide, 28.5 g. (0.15 mol. of fi-methoxy-B-aminolepidine, 25 g. (0.3 mol.) of sodium acetate, and 90 ml. of percent alcohol is reflexed for about 48 hours. The solution is poured into about 500 ml. of water and made alkaline with ,potassium hydroxide. This liberates as a free base the desired 6-methoxy-8- (6'-diethylaininohexylammql -lepidine; This is recovered by extraction w-itl i ether anddistillation of the ether extract in an inert atmosphere, conveniently nitrogen, at a pressure of about 0.5 mm. or less,- with a bath temperature of about 225-250 C. yields about 19.1 g. of the desired, 6.-.methoxy-8 -(6' diethylaminohexylamino)V-lepidine, boiling at about l90-200 C. at 0.05

pressure.

To convert. thist'o; its dihydrochloride, the free base, dissolved'inabout 50 ml. of n-lpropanol, is titrated with propanolic hydrogen chloride. This produces a yellow crystalline precipitate, melting-at about I'M-178 C., which is the desired 6- methoxy -8- (6-diethylaminohexylamino) lepidine dihydrochloride. This may be recrystaliz from r p no o y e d, a. pr duc m l ing at about, ITS-180" C.

To. obtain the corresponding filiydroxy-fi -ifif diethylaminohexylamino).-lepidine, the G-meth-r oxyv compound} obtained above, may be refluxed for aboutiour hours with a 50. percent; solution,

of hydrogen bromide, the reaction mixture evaporated to dryness, and the residue recrystallizedfrom alcohol-ether. This produces the G-hydroxy 8 (6 diethylaminohexylamino) lepidine in the form of its dihydrobromide.

Example 2 6 methoxy 8 (1' methyl 4' lsopropylaminobutylamino) -lepidine', represented by the following formula,

of 6 methuxy ii-anunolepidine" is hel'dF at a temperature' of about 45Gi' for a periodoiab'ouir 12-14 hours. The temperature is then increased;

to 60 C. for one hour, then to C. for one hour, and finally to 915 C: for about five to six hours. The; reaction mixture while still hot is poured into. 1 liter of cold water, and

treated with 1 liter" of 40 percent potassium hydroxide solution. This liberates as a free base the desired. 6+methoxy-ih-(ll-methylfii-isgpro pylaminobutylamino) -lepidine-,. oi. formula,6.. Tb. j

efiect its recovery, the reaction mixture is extracted with ether, desirably with successive por-- tions of ether. The ether'extracts are combined and extracted with a buffer solution prepared by adding sodium acetate to a 10 percent solution of acetic acid untilthe solution gives a neutral or very slightly basic test on Congo red paper. The extraction with the buffer solution is continued until no strong coloration of the-aqueous layer is observed. The combined buffer extracts are extracted with three 100 ml. portionsof ether and then treated with an equal volumeof 40 percent aqueous potassium hydroxide. The mixture is extracted with ether. The ether solution is dried, as over magnesium sulfate, filtered, and concentrated on a steam bath. The residue is distilled in an inert atmosphere at less than 0.5 mm. pressure with a bath temperature of about 225-250 C., and yields a purified form of the desired 6-methoxy-8-(1-methyl-4'-isopropylaminobutylamino) -lepidine.

This may be converted to its hydrochloride, or to the correspoding 6-hydroxy compound, by the procedures set forth in Example 1.

Example 3 6-methoxy-8- (5' isopropylaminoamylamino) lepidine represented by the following formula Etc 0- 6-methoxy-8-(3' diethylaminopropylamino) lepidine represented by the following formula may be prepared by the procedure of Example 1, save that diethylaminopropyl bromide hydrobromide is used instead of diethylaminohexyl bromide hydrobromide. As in Example 1, the substituted lepidine may be converted to its dihydrochloride, or may be demethylated to yield the corresponding 6-hydroxy compound.

Example 6 methoxy 8 (4' ethylaminohexylamino) lepidine, represented by the following formula may be prepared by the procedure of Example 1, save that instead of diethylaminohexyl bromide hydrobromide, the hydrobromide of 1-bromo-4- ethylaminohexane is used. This latter compound 6 is described by Elderfield et at, J. chem; Soc. 68, pages 1579-1584 (1946). As in Example 1, the substituted lepidine may be converted to its dihydrochloride, or may be demethylated to yield the corresponding G-hydroxy compound.

Example 6 6 methoxy s (1' methyl 4' dlethylaminobutylamino)- 1epidine, represented by the following formula may be prepared by the procedure of Example 2, save that instead of 1-methyl-4-isopropylaminobutyl bromide hydrobromide, l-methy1-4-diethy1- aminobutyl bromide hydrobromide is used. in Example 1, the substituted lepidine may be converted to its dihydrochloride, or may be demethylated to yield the corresponding G-hydroxy compound. 1

Example 7 6 methoxy 8 (6' butylaminohexylamino) lepidines, represented by the following formula may be prepared by the procedure of Example 1,-

Example 8 By the procedures of the foregoing examples, other 6-methoxyand G-hydroxy-B-(alkylaminoalkylamino) -lepidines and their dihydrochlorides may be prepared, by the use of other alkylaminoalkyl halides of Formula 4 or their hydrohalides.

Example 9 Any of the preceding examples may be repeated, save that instead of using 6-methoxy-8- aminolepidine, other 6-alko-xy-8-aminolepidines may be used, to produce corresponding 6-alkoxy- S-(alkylaminoalkylamino) -lepidines.

Ewample 10 Any of the preceding examples may be repeated, save that instead of forming the dihydrochlorides of the substituted lepidines produced, other salts thereof may be formed, such for example as the hydrobromides, the phosphates, the cltrates, etc.

i-itclaim as my invention:

'1. The new .antimalarials :from the group consisting of the free base represented by theicllow in iomnula in which R is an alkyl radical having from 2 to 8 carbon atoms, R1 is a member-pf the class consisting of hydrogen and alkyl radicals having from 1 to 6 carbon atoms, R2 is an alkyl radical having from 1 t 6 carbon atoms, and R3 is an alkyl radical having from 1 to i carbon atoms; and their salts.

'2. The new antimalarials from the group consisting of the free base, comprising that, ti-substituted lepidine represented by the following formula 1 N 01134 HN (CH1) e-N\ and their salts.

3. The process of producing the new antimalarials as defined in claim 1, which comprises condensing an o-nitro-p-alkoxy aniline and methylvinyl ketone with arsenic acid and concentrated sulfuric acid, to form a fi-alkoxy-S- nitrolepidi-ne, reducing said 8-nitro compound to 8 the corresponding amino compound, and condensing said .B- amhio compound with a com pound :of the class consisting of alkylaminoalkyl halides the following formula Number Name Date 1,747,531 Schulemannet a1. Feb. 18, 1930 1,806,564 Prill et a1. May 19, 1931 1,879,538 Schonhofer Sept. 27, 1932 1,938,047 Schonhofer et a1. Dec. 5, 1933 FOREIGN PATENTS Number Country Date 267,457 Great Britain Mar. 27, 1927 3883087 Great Britain Feb. 23, 1933' :OTHER REFERENCES Hollins: The Synthesis of Nitrogen Ring Qempcunds (11 Van Nostrand; New York; I924"), page 252.

Williams: Chemotherapy of Malaria, page 86 (pubfished by Lederle Laboratories, Inc., New York, N.Y., June 1941).

Shriner et a1.: Synthetic Antimalarials, page 18 (published at Bloomington, Indiana, 1941). 

1. THE NEW ANTIMALARIALS FROM THE GROUP CONSISTING OF THE FREE BASE REPRESENTED BY THE FOLLOWING FORMULA 